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Aprepitant is an FDA-approved medication for chemotherapy-induced nausea and vomiting. It blocks substance P binding to neurokinin-1; substance P has been implicated in itch pathways both as a local and global mediator.
Song et al BMC Cancer (2017) 17:200 DOI 10.1186/s12885-017-3194-8 CASE REPORT Open Access Aprepitant for refractory cutaneous T-cell lymphoma-associated pruritus: cases and a review of the literature Johanna S Song1,3,4, Marianne Tawa2, Nicole G Chau3, Thomas S Kupper1,2,4 and Nicole R LeBoeuf1,2,4* Abstract Background: Aprepitant is an FDA-approved medication for chemotherapy-induced nausea and vomiting It blocks substance P binding to neurokinin-1; substance P has been implicated in itch pathways both as a local and global mediator Case presentations: We report a series of four patients, diagnosed with cutaneous T-cell lymphoma, who experienced full body pruritus recalcitrant to standard therapies All patients experienced rapid symptom improvement (within days) following aprepitant treatment Conclusion: Aprepitant has been shown in small studies to be efficacious for treating chronic and malignancy-associated pruritus Prior studies have shown no change in clinical efficacy of chemotherapeutics with concurrent aprepitant administration These cases further demonstrate that aprepitant can be considered as a therapeutic option in malignancy-associated pruritus and further support the need for larger clinical trials Keywords: Cutaneous T-cell lymphoma, Aprepitant, Emend, Pruritus, Itch, Case report Background Aprepitant (Emend; Merck & Co Inc) has been approved for use as an antiemetic in patients receiving chemotherapy It blocks the binding of substance P to its receptor, neurokinin-1, which plays a role in pathways that induce nausea and vomiting Recently in the literature, there have been multiple successful case reports of aprepitant use for pruritus We report four cases of successful use of aprepitant for generalized pruritus in patients diagnosed with cutaneous T-cell lymphoma (CTCL) and review the available clinical literature Case presentation A 51-year-old woman presented with a 1.5-year history of lymphomatoid papulosis and extensive cutaneous anaplastic large cell lymphoma The patient had experienced severe full-body itch with the diagnosis of her disease, * Correspondence: NLEBOEUF@partners.org Prior Presentation: This work was presented at the Multinational Association of Supportive Care and Cancer Meeting, Miami FL, June 26–28, 2014 Department of Dermatology, Brigham and Women’s Hospital, 221 Longwood Ave., Boston, MA 02115, USA Center for Cutaneous Oncology, Dana-Farber Cancer Institute, 450 Brookline Ave., Boston, MA 02215, USA Full list of author information is available at the end of the article which was moderately responsive to prednisone She had previously been treated for her lymphoma with methotrexate and NB-UVB with no improvement in disease or itch PUVA was tried and discontinued because of bullae development She subsequently completed eight cycles of brentuximab, but had disease progression off treatment She was then started on a clinical trial with an inhibitor of program death receptor (PD-1), but was taken off the trial due to progressive disease Itch persisted throughout her disease course She began treatment with single-agent gemcitabine weeks prior to the initiation of aprepitant and had persistent itch and disease with this On exam, she had multiple erythematous and skincolored papules and plaques on her face, upper extremities, trunk and neck She had no lymphadenopathy Laboratory findings including serum chemistries, blood urea nitrogen, complete blood cell count, thyroid and liver function were normal Treatment with oral aprepitant, day 1, 125 mg; day 2, 80 mg; day 3, 80 mg was initiated with cycle 3, day of gemcitabine chemotherapy (administered days 1, of a 28 day cycle) Her symptoms improved three hours after aprepitant treatment from 10/10 to 0/10 for five days, but then her pruritus returned at 4/10 and increased thereafter © The Author(s) 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated Song et al BMC Cancer (2017) 17:200 until she took her next aprepitant dose with chemotherapy On weeks where she did not take aprepitant, days 16–28, she experienced severe pruritus She completed three cycles of gemcitabine with minimal response in her disease Three weeks after aprepitant initiation, she underwent electron beam radiation therapy and began romidepsin Aprepitant dosing was adjusted to every other day, with pruritus reaching 5/10 before the next dose and pruritus relief to 0/10 following every dose Three months after aprepitant initiation, due to increased disease burden, brentuximab chemotherapy and surface conformal brachytherapy were initiated Aprepitant dosing was then adjusted to every three days due to attempt to prolong reduced itch periods, as insurance coverage was challenging; she continued with pruritus reduction ranging from 4/10 to 0/10 for year using this regimen Three additional patients with cutaneous T-cell lymphoma (CTCL) were treated with aprepitant for pruritus The clinical findings of these patients are shown in Table Discussion Itch in the oncology patient presents an additional challenge that may dramatically affect quality of life in those already facing a cancer diagnosis and adverse effects from antineoplastic therapies Pruritus is thought to be a multifactorial symptom that may be induced by local skin immune responses as well as global neurological pathways Local cutaneous pathways are mediated by itchselective C nerve fibers, whose signals are augmented by local T cells, mast cells, cytokines and neuropeptides The C nerve fibers synapse with second-order projections, which continue to transmit signals to the thalamus for processing [1] Aprepitant, approved for use in chemotherapy-induced nausea and vomiting in 2003, has been used with increasing frequency for this indication both as a stand-alone treatment and as part of combination regimens This medication is well tolerated In a systematic review including 8740 patients treated with aprepitant, statistically significant differences in fatigue and hiccups as well as infections were seen; of note the patients contributing to increased infections were from a single study where high doses of dexamethasone were used concomitantly [2, 3] Aprepitant is a neurokinin-1 (NK1) receptor antagonist that can cross the blood-brain barrier; it prevents substance P from binding to its NK1 receptor Substance P, a tachykinin neuropeptide, mediates nausea pathways in the brainstem as well as itch pathways from the skin to spinal cord [4] Injected substance P into the skin of non-atopic patients induces an itch response in normal and inflamed skin [5] Atopic dermatitis patients have been observed to have increased substance P-positive and NK1 receptor- Page of immunoreactive nerve fibers as compared to healthy controls [6] Substance P has been shown to bind NK1 receptors on keratinocytes, which activate mast cell degranulation and release of cytokines and chemokines such as histamine, prostaglandin D2 and leukotriene B4, which mediate itch [7] NK1 receptors are also present in rat dorsal horn neurons, which may play a role in neurologic itch [8] The importance of these neurotransmitters specifically in oncology patients has not been studied and their roles require further research Pruritus is sometimes a non-specific presenting complaint of underlying malignancy While this is most often described with Hodgkin’s disease, it is also reported with many solid tumors such as those originating in the breast, gastrointestinal system and liver In small studies of patients with non-specific generalized itching, underlying malignancy was found to be the cause of itch in fewer than 10% of patients [9] Appropriate assessment of true, diffuse pruritus symptoms includes an age and symptom appropriate malignancy evaluation The pathophysiology of malignancy and itch has yet to be clearly elucidated; however, many mediators have been suggested to play a role Recent studies propose that the T-cell dysregulation associated with Hodgkin’s lymphoma contributes to high rates of pruritus associated with this malignancy [10] and the cytokines IL-6, IL-8, and IL-31 may also play roles in lymphoma-associated or chronic itch [9] In our reported cases, patients suffered from cutaneous lymphoma, which unlike pruritus without a rash, has multiple potential contributors to itch symptoms These patients were concurrently treated for their primary malignancy with variable response Although malignancy treatment may also relieve pruritus, in all of our cases, patients had previously failed conventional treatments for itch for many months prior Our cases also reported pruritus cessation within hours to days after aprepitant treatment, in the setting of progressive or persistent malignancy, suggesting that aprepitant has a direct effect on symptom relief Prior reports also suggest that patients suffered rebound itch upon cessation of aprepitant with continuation of chemotherapy, suggesting a role for aprepitant’s direct involvement in pruritus relief Aprepitant is metabolized through the cytochrome P450 system, specifically CYP3A4 It moderately inhibits CYP3A4, induces CYP2C9 and possibly affects other isoenzymes As such, medication interactions, specifically with chemotherapeutic drugs metabolized by these enzymes should always be considered [11] However, studies in patients concurrently treated with aprepitant and docetaxel, vinorelbine or cyclophosphamide have not shown clinically significant decreases in chemotherapeutic serum concentrations [12] To date, at least 74 patients in the literature have been reported to experience pruritus relief with aprepitant treatment (Table 1) In prospective studies, pruritus relief 2 1 24 Vincenzi et al (2010) [21] Vincenzi et al (2010) [22] Booken et al (2011) [15] Mir et al (2011) [23] Ladizinski et al (2012) [24] Santini et al (2012) [14] 1 Borja-Consigliere et al (2014) [27] Jimenez Gallo et al (2013) [26] Villafranca et al (2014) [28] 41 1 2 Torres et al (2012) [25] 21 Duval et al (2009) [20] Complete Partial Partial Partial Partial Partial Complete Partial Partial Partial Partial Complete Partial Complete Partial Mean 9.8 to 4.3 to to to to to to to Response by Scale NRS VAS VAS VAS VAS VAS VAS 10 to to after two weeks, then to after one month 10 to 10 to to to Median, to Median, to 10 to Subjective Pruritus regressed VAS VAS VAS VAS No of total No of responding Complete vs Itch Scale patients patients partial response Patients with Malignancy Associated Itch Source (year) Table Clinical characteristics of patients with symptoms of itch treated with aprepitant therapy 51 M CTCL, MF 51F 27F 61F 41F N/A Hodgkin’s lymphoma CTCL CTCL, MF CTCL, SS 45-70 M/F Naïve to treatment, metastatic solid tumor 42-76 M/F Refractory itch, metastatic solid tumor 66 M NSCLC on erlotinib CTCL, MF 65 M 54, N/A CTCL, SS CTCL, SS 65F CTCL, SS Metastatic breast carcinoma Metastatic soft tissue sarcoma NSCLC on erlotinib CTCL, SS Primary cause of itch 56F N/A, F N/A, M 74 M 44F N/A Age, y/ sex 7d Length of treatment 80 mg/d d1: 125 mg; d2, 3: 80 mg; every weeks d1: 125 mg; d2, 3: 80 mg; every weeks 80 mg/d d1: 125 mg; d3, d5: 80 mg 80 mg/d; 3×/ week 80 mg/d d1: 125 mg; d2, 3: 80 mg; every weeks d1: 125 mg; d2, 3: 80 mg 1m 13m N/A 15d, then every other d for 10d 1w 4m 14d Median 15w (range 6–24) 3d d1: 125 mg; d2, 2m 3: 80 mg; then 125 mg, 80 mg alternating 80 mg/d Dose of aprepitant Song et al BMC Cancer (2017) 17:200 Page of Partial 20 Stander et al (2010) [13] 16 Partial Complete Partial VAS 52F 78 M 72 M 36 M 72 M 66F 69 M 82F 81F 85F to to to to to to 10 to to 10 to 10 to 10 to 73F 55F 10 to 59F 10 to 50F 42 M to to 66F 61F to Subjective Vast improvement 59 M Unknown Unknown Multifactorial (renal, hyperuricemia) Renal Multifactorial (renal, dry skin) Renal Unknown Unknown Renal Unknown Multifactorial (cholestatic, dry skin, psychosomatic factors) Multifactorial (renal, diabetes) Multifactorial (metabolic syndrome) Multifactorial (thyroid dysfunction, neurogenic) Unknown Multifactorial (hyperuricemia, iron deficiency) Brachioradial pruritus 80 mg/d 80 mg/d 6.6d (range 3–13) 2w 1m every 2w for 10m 10 to CTCL, MF 3w; then every 3d for 12m every 2w for 6m 68F d1: 125 mg; d2, d3: 80 mg 10 to 2; during non-treatment 64 M weeks pruritus increased back to 10 10 to 6; after months to 2; during non-treatment weeks pruritus increases to CTCL, lymphomatoid papulosis/cutaneous anaplastic lymphoma Abbreviations: N/A not available, d days, w weeks, m months, y years, VAS visual analogue scale, NRS numeric rating scale, CTCL cutaneous T-cell lymphoma, SS Sezary syndrome, MF mycosis fungoides, NSCLC non-small cell lung cancer Ally et al (2013) [29] Patients with Chronic Itch, Non-malignancy Associated Present cases (2017) Table Clinical characteristics of patients with symptoms of itch treated with aprepitant therapy (Continued) Song et al BMC Cancer (2017) 17:200 Page of Song et al BMC Cancer (2017) 17:200 has been reported in 80–91% of patients, suggesting that aprepitant may be uniquely effective against itch, especially in patients with symptoms refractory to standard treatments [13–15] Because itch pathways have not been fully elucidated and are likely activated through more than one process in the oncology patient with inflammatory skin lesions, deactivating itch likely requires a multifaceted approach With persistence of an inflammatory malignancy, the trigger of the itch response persists and it is expected that the itch will recur In addition, chemotherapeutic regimens may result in modified pathways via effects on the skin and small nerve fibers When multiple potential causes of itch exist, combination therapy with conventional anti-itch agents may be helpful; emollients, topical steroids, antihistamines, gabapentin, pregabalin, mirtazapine, ultraviolet light and tricyclic antidepressants should be considered depending on patient findings, comorbidities and with consideration of medication interactions These can be adjusted to bridge non-aprepitant days and in instances of treatment delays due to medication access In small studies, aprepitant has been shown to be both safe and effective in treatment of malignancy-associated and refractory chronic pruritus In 10 patients with an atopic diathesis, aprepitant reduced itch >40% in 9/10 patients [13] Further research is needed to evaluate the patient population most likely to respond to aprepitant for pruritus, as it may be a tool for malignancy-associated itch, as well as in inflammatory conditions associated with chronic pruritus However, as demonstrated in our table, there is significant heterogeneity in dosing regimens and duration of treatment Practitioners have prescribed dosing either as 80 mg daily or in a tri-fold pack of 125 mg/ 80 mg/80 mg for days to 24 weeks While further studies are needed to determine the most effective dosing regimen in oncology patients, of the previous reports of six patients treated with aprepitant 80 mg daily, none experienced a complete response in pruritus In our patients, we use tri-fold dosing of 125 mg/80 mg/80 mg, administered weekly if itch recurs after the first doses Given that our patients experienced an increase in pruritus symptoms on days without aprepitant treatment, until larger dosing studies are available, we continue treatment while patients are experiencing relief, as cessation may cause itch to return to baseline levels These cases demonstrate that the use of aprepitant may be helpful in patients with CTCL who experience pruritus refractory to conventional treatments An estimated 66– 88% of CTCL patients report experiencing pruritus with effects on quality of life [16, 17] Reports that included Dermatology Life Quality Index (DLQI) score along with the visual analogue scale (VAS) demonstrated a high correlation between the two measures Patients who experienced large improvements in pruritus symptoms by VAS Page of had similar dramatic decreases in DLQI scores The VAS is a commonly used tool for quantifying itch It has been validated in patients with chronic itch or pruritic dermatoses with a high correlation with the numeric rating scale [18, 19] Future studies exploring how itch impacts patient quality of life and the effectiveness of interventions such as aprepitant should consider patient-reported outcomes A disease-specific scale may be of significant use in the oncology population Conclusion We observed cases of significant pruritus improvement in CTCL patients treated with aprepitant, supporting that this modality can be useful in treating some patients with malignancy-associated itch refractory to conventional treatments There continues to be a need for larger comparative effectiveness trials of aprepitant in patients with chronic, malignancy and treatment-associated itch Review of the literature demonstrated discrepancies in dose and timing of aprepitant regimens as well as outcome measures; prospective studies should evaluate dosing to discern the most effective administration schedule Future study is imperative as oncology patients may experience negative impact on quality of life from treatment refractory pruritus Abbreviations CTCL: Cutaneous T-cell lymphoma; DLQI: Dermatology Life Quality Index; NK1: Neurokinin-1; VAS: Visual analogue scale Acknowledgements The authors have no acknowledgements Funding No funding was acquired for this study Availability of data and materials The datasets generated and/or analyzed during the current study are not publicly available as they are patient information in an electronic medical record but are available from the corresponding author on reasonable request Authors’ contributions NRL conceived the study, takes full responsibility of the manuscript, and oversaw all drafts of the manuscript JSS, MT, NGC, and TSK reviewed patient charts JSS drafted the majority of the manuscript All authors were involved in drafting the manuscript All authors read and approved the final manuscript Competing interests Dr Kupper serves on the advisory board for Adaptive Biotechnologies All other authors including Dr Song, Ms Tawa, Dr Chau, and Dr LeBoeuf have no conflict of interest to declare Consent for publication Written informed consent was obtained from all patients for publication of this case series and any accompanying images A copy of the written consent is available for review Ethics approval and consent to participate This study was approved by the Brigham and Women’s and Dana Farber Cancer Institute IRB Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations Song et al BMC Cancer (2017) 17:200 Author details Department of Dermatology, Brigham and Women’s Hospital, 221 Longwood Ave., Boston, MA 02115, USA 2Center for Cutaneous Oncology, Dana-Farber Cancer Institute, 450 Brookline Ave., Boston, MA 02215, USA Center for Head and Neck Cancer, Dana-Farber Cancer Institute, 450 Brookline Ave., Boston, MA 02215, USA 4Harvard Medical School, 25 Shattuck St., Boston, MA 02115, USA Received: January 2017 Accepted: 11 March 2017 References Yosipovitch G, Bernhard JD Clinical practice Chronic pruritus N Engl J Med 2013;368(17):1625–34 dos Santos LV, Souza FH, Brunetto AT Sasse AD, da Silveira Nogueira Lima JP: Neurokinin-1 receptor antagonists for chemotherapy-induced nausea and vomiting: a systematic review J Natl Cancer Inst 2012;104(17):1280–92 Chawla SP, Grunberg SM, Gralla RJ, Hesketh PJ, Rittenberg C, Elmer ME, Schmidt C, Taylor A, Carides AD, Evans JK, et al Establishing the dose of the oral NK1 antagonist aprepitant for the prevention of chemotherapy-induced nausea and vomiting Cancer 2003;97(9):2290–300 Wallengren J Neuroanatomy and neurophysiology of itch Dermatol Ther 2005;18(4):292–303 Thomsen JS, Sonne M, Benfeldt E, Jensen SB, Serup J, Menne T Experimental itch in sodium lauryl sulphate-inflamed and normal skin in humans: a randomized, double-blind, placebo-controlled study of histamine and other inducers of itch Br J Dermatol 2002;146(5):792–800 Pincelli C, Fantini F, Massimi P, Girolomoni G, Seidenari S, Giannetti A Neuropeptides in skin from patients with atopic dermatitis: an immunohistochemical study Br J Dermatol 1990;122(6):745–50 Kulka M, Sheen CH, Tancowny BP, Grammer LC, Schleimer RP Neuropeptides activate human mast cell degranulation and chemokine production Immunology 2008;123(3):398–410 Carstens EE, Carstens MI, Simons CT, Jinks SL Dorsal horn neurons expressing NK-1 receptors mediate scratching in rats Neuroreport 2010;21(4):303–8 Yosipovitch G Chronic pruritus: a paraneoplastic sign Dermatol Ther 2010; 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Partial Partial Partial Partial Partial Complete Partial Partial Partial Partial Complete Partial Complete Partial Mean 9.8 to 4. 3 to to to to to to to Response by Scale NRS VAS VAS VAS VAS VAS... any accompanying images A copy of the written consent is available for review Ethics approval and consent to participate This study was approved by the Brigham and Women’s and Dana Farber Cancer... scale Acknowledgements The authors have no acknowledgements Funding No funding was acquired for this study Availability of data and materials The datasets generated and/ or analyzed during the